The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years (Science 1983, 220, 868-871; N. Eng. J. Med. 1984, 311, 1292-1297). AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells. HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.
The natural compound betulinic acid, isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity. Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 199457(2):243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that bevirimat acts by disrupting Gag processing (Proc. Natl. Acad. Sci. USA 2003, 100(23):13555-60; Antimicrob. Agents. Chemother. 2001, 45(4), 1225-30; J. Virol. 2004, 78(2): 922-9; J. Biol. Chem. 2005, 280(51):42149-55; J. Virol. 2006, 80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given bevirimat have a robust viral load reduction. It was reported that non-respondent patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines treatment response to bevirimat. XVII international HIV drug resistance work shop Jun. 10-14, 2008, Sitges, Spain).
Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/105926 describes novel betulinic acid proline derivatives as HIV inhibitors; WO 2013/160810 describes novel betulinic acid derivatives as HIV inhibitors; Journal of Medicinal Chemistry (2012), 55(18), 8128-8136 describes Novel C-28 modified bevirimat analogues as potent HIV maturation inhibitors; WO 2011/153319 describes C-28 amides of modified C-3 betulinic acid derivatives as HIV maturation inhibitors; WO 2011/153315 describes modified C-3 betulinic acid derivatives as HIV maturation inhibitors; WO 2011/007230 describes lupeol-type triterpene derivatives as antivirals; WO 2010/132334 describes 3, 28-disubstituted betulinic acid derivatives as anti-HIV agents; Journal of Medicinal Chemistry (2009), 52(10), 3248-3258 describes Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents; WO 2009/082819 describes novel lupane derivatives; WO 2009/100532 discloses novel 17 β lupine derivatives as anti-HIV agents; Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 24, 15 Dec. 2008, Pages 6377-6380 describes triterpene based compounds with potent anti-maturation activity against HIV-1; The patent publication WO 2008/057420 describes extended triterpene derivatives as antiretroviral agents; WO 2007/141391 describes betulin derived compounds useful as antiprotozoal agents; WO 2007/141390 describes preparation of betulin derived compounds as antiviral agents; WO 2008/127364 describes preparation of betulinic acid derivatives for use in antiviral and anticancer pharmaceutical compositions; US 2008/0207573 describes preparation of triterpene derivatives for therapeutic use in the treatment of viral infections; WO 2007/141389 describes preparation of betulin derived compounds as antibacterial agents; US 2004/0204389 describes anti-HIV agents with dual sites of action; WO 2007/002411 describes antiviral compounds; CN 1861627 describes antitumor agents; WO 2006/053255 describes novel betulin derivatives, preparation and use thereof; WO 2009/082818 describes novel C-21 keto lupine derivatives preparation and use thereof; and WO 2006/105356 describes methods of manufacturing bioactive 3-esters of betulinic aldehyde and betulinic acid.
Some additional references disclose betulinic acid related compounds. For example, WO 2007/141383 describes betulin derivatives as antifeedants for plant pests; U.S. Pat. No. 6,670,345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid; WO 2002/091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use; WO 2000/046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors; WO 2007/141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives; and Pharmaceutical Chemistry Journal, 2002, 36(9), 29-32 describes synthesis and anti-inflammatory activity of new acylated betulin derivatives.
Given the fact of the world wide epidemic level of AIDS, there is a strong continued need for new effective drugs for treatment of HIV infected patients, disease conditions and/or disorders mediated by HIV by discovering new compounds with novel structures and/or mechanism of action(s).